Individuals with non-insulin dependent diabetes mellitus have both insulin resistance and abnormal islet cell function in response to glucose. Which of these lesions is a primary defect remains controversial. One way to address this question is by studying the effect of insulin resistance on beta-cell function in individuals with normal islet cell function, and with no family history of diabetes, to determine if islet function "normally" deteriorates in response to insulin resistance. In this study, insulin resistance was induced by administration of nicotinic acid in young, lean, healthy Caucasian males with no family history of diabetes. Nicotinic acid induced severe degrees of insulin resistance and marked deterioration in glucose tolerance. Insulin secretion increased in response to the insulin resistance but was not sufficient to overcome the insulin resistance, thereby, resulting in the deterioration of glucose tolerance. These data suggest that a "normal" pancreas does not fully compensate for insulin resistance.